Angiogenesis promoters and angiogenesis potentiators

ABSTRACT

An angiogenesis promoter and angiogenesis potentiator containing a pyridazinone compound of the formula (I)                    
     wherein each symbol is as defined in the specification, or a pharmacologically acceptable salt thereof, as an active ingredient. The pyridazinone compound (I) and a pharmacologically acceptable salt thereof in the present invention promote angiogenesis and potentiate the angiogenic effect of a drug having such effect, and are useful as an angiogenesis promoter and angiogenesis potentiator.

TECHNICAL FIELD

The present invention relates to angiogenesis promoters and angiogenesispotentiators, which contain, as an active ingredient, a specificpyridazinone compound or a pharmacologically acceptable salt thereof.

BACKGROUND ART

The below-noted specific pyridazinone compound in the present inventionis known to have superior platelet aggregation inhibitory effect,cardiotonic effect, vasodilating effect, anti-SRS-A (Slow ReactingSubstances of Anaphylaxis) effect, thromboxane A₂ synthase inhibitoryeffect and the like (JP-B-7-107055, JP-A-7-285869), and is a drugexpected to be an antiplatelet agent and the like.

However, there has not been any report on the effect of the pyridazinonecompound on angiogenesis.

DISCLOSURE OF THE INVENTION

The present inventors have conducted various studies of the effect ofthe pyridazinone compound on the angiogenesis and found that thepyridazinone compound promotes angiogenesis and potentiates anangiogenic effect of a drug having such effect, which resulted in thecompletion of the present invention.

Accordingly, the present invention provides the following.

An angiogenesis promoter containing a pyridazinone compound of theformula (I)

wherein R¹, R² and R³ are each independently a hydrogen atom or a loweralkyl, X is a halogen atom, cyano or a hydrogen atom, Y is a halogenatom, trifluoromethyl or a hydrogen atom, and A is C₁-C₈ alkyleneoptionally substituted by hydroxyl group, or a pharmacologicallyacceptable salt thereof (hereinafter to be referred to as pyridazinonecompounds) as an active ingredient.

A method of promoting angiogenesis, which comprises administering apyridazinone compound.

Use of a pyridazinone compound for the production of an angiogenesispromoter.

A pharmaceutical composition for promoting angiogenesis, which comprisesa pyridazinone compound and a pharmaceutically acceptable carrier.

A commercial package comprising the above-mentioned pharmaceuticalcomposition, and a written matter associated therewith, the writtenmatter stating that the pharmaceutical composition can or should be usedfor promoting angiogenesis.

A potentiator of a drug having an angiogenic effect, which contains apyridazinone compound as an active ingredient.

A method of potentiating an angiogenic effect of a drug having sucheffect, which comprises administering a pyridazinone compound.

Use of a pyridazinone compound for the production of a potentiator of adrug having an angiogenic effect.

A pharmaceutical composition for potentiating an angiogenic effect of adrug having such effect, which contains a pyridazinone compound and apharmaceutically acceptable carrier.

A commercial package comprising the above-mentioned pharmaceuticalcomposition, and a written matter associated therewith, the writtenmatter stating that the pharmaceutical composition can or should be usedfor potentiating an angiogenic effect of a drug having such effect.

The pyridazinone compound in the present invention is preferably acompound of the formula (I), wherein R¹ and R² are each hydrogen atom,R³ is hydrogen atom or alkyl having 1 to 4 carbon atoms, X is halogenatom, Y is halogen atom or hydrogen atom and A is C₁-C₅ alkyleneoptionally substituted by hydroxyl group.

Particularly preferable pyridazinone compound of the formula (I)(hereinafter to be referred to as pyridazinone compound (I)) is, forexample,4-bromo-6-[3-(4-chlorophenyl)-propoxy]-5-(3-pyridylmethylamino)-3-(2H)-pyridazinone.

Angiogenesis means that endothelial cells bud from an existing bloodvessel and form a new blood vessel. The process of the formation iscomplicated and is an important phenomenon observed in various aspectsin the living body, such as angiogenesis for development and growth,pathologic angiogenesis (e.g. growth of tumor, diabetic retinopathy) andthe like.

Administration of an angiogenesis promoter to the patients with canceror diabetic retinopathy is prohibited because it promotes pathologicangiogenesis.

However, an angiogenesis promoter is useful in that it complements andpotentiates the efficacy of a pharmaceutical agent that directly acts onthe mainly diseased artery (artery mainly causing the disease), becauseit forms a collateral circulatory path irrespective of the mainlydiseased artery.

The symbols used in this specification are explained in the following.

The lower alkyl at R¹, R² and R³ has 1 to 6 carbon atoms and may belinear or branched. Examples thereof include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and thelike.

R¹ and R² are each preferably a hydrogen atom and R³ is preferably ahydrogen atom or alkyl having 1 to 4 carbon atoms.

The alkyl having 1 to 4 carbon atoms at R³ is exemplified by methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl andthe like.

The halogen atom at X and Y means fluorine atom, chlorine atom, bromineatom or iodine atom.

Preferable X is a halogen atom and preferable Y is a halogen atom and ahydrogen atom.

The C₁-C₈ alkylene optionally substituted by hydroxyl group at A may belinear or branched and is exemplified by methylene, ethylene, propylene,butylene, pentylene, hexylene, heptylene, octylene,2,2-dimethylethylene, 2,2-diethylethylene, 2,2-di-n-propylethylene,hydroxymethylene, 1-hydroxyethylene, 2-hydroxyethylene,3-hydroxypropylene and the like.

Preferable A is C₁-C₅ alkylene optionally substituted by hydroxyl group.

In the formula (I), methylene group and pyridine ring may be bonded atany position, but preferably bonded at the 3-position relative to thenitrogen atom of the pyridine ring.

Y may be substituted at any position on the benzene ring, but preferablyat the 4-position.

Particularly, the pyridazinone compound of the formula (I) wherein R¹and R²are hydrogen atoms, R³ is hydrogen atom or alkyl having 1 to 4carbon atoms, X is halogen atom, Y is halogen atom or hydrogen atom andA is C₁-C₅ alkylene optionally substituted by hydroxyl group ispreferable.

More preferable pyridazinone compounds (I) include4-bromo-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-chloro-6-(3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-chloro-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-bromo-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-chloro-6-(2,2-dimethyl-3-phenylpropoxy)-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-bromo-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-chloro-6-[3-(4-chlorophenyl)-2,2-dimethylpropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-bromo-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-chloro-6-[3-(4-chlorophenyl)-3-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone,4-bromo-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinoneand4-chloro-6-[3-(4-chlorophenyl)-2-hydroxypropoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.

The pyridazinone compound (I) in the present invention encompassesstereoisomers and optical isomers.

The pyridazinone compound (I) can be produced by a method disclosed in,for example, JP-B-7-107055, U.S. Pat. No. 5,314,883, EP-A-482208,JP-A-7-252237, U.S. Pat. No. 5,750,523 and EP-A-742211.

The pharmacologically acceptable salts of pyridazinone compound (I)include salts with inorganic acid (e.g., hydrochloride, hydrobromide,phosphate, sulfate and the like), salts with organic acid (e.g.,acetate, succinate, maleate, fumarate, malate, tartrate and the like),and the like.

The pyridazinone compound (I) can be converted to the above-mentionedsalts by known methods.

The pyridazinone compound (I) and pharmacologically acceptable saltsthereof can be used as an angiogenesis promoter by themselves. They maybe also used as a potentiator of the angiogenic effect of a drug havingsuch effect by concurrently using the drug.

The drug having an angiogenic effect may be a growth factor such as abasic fibroblast growth factor;b-FGF, an endothelial cell growthfactor;ECGF, an epidermal growth factor;EGF, a transforming growthfactor-β;TGF-β, a platelet-derived endothelial cell growth factor;PDGF,a vascular endothelial growth factor;VEGF, a vascular permeabilityfactor;VPF and the like, heparin, adenosine and the like.

The pyridazinone compound (I) and pharmacologically acceptable saltsthereof are superior as a potentiator of the angiogenic effect of agrowth factor, particularly b-FGF.

The effects of the present invention can be confirmed by any knownmethod which is free of limitation.

The pyridazinone compound (I) and pharmacologically acceptable saltsthereof, which are the active ingredients in the present invention, areextremely low toxic and show an angiogenesis-promoting effect andpotentiation of the angiogenic effect of a drug in mammals such ashuman, dog, cow, horse, rabbit, mouse, rat and the like.

The pyridazinone compound (I) and pharmacologically acceptable saltsthereof can be administered parenterally in the form of injection(subcutaneous, intravenous, intramuscular, intraperitoneal injections),ointment, suppository, aerosol agent and the like, or orally in the formof tablet, capsule, granule, pill, syrup, liquid, emulsion, suspensionand the like.

The pyridazinone compound (I) and salts thereof can be formulated into apreparation for administration, according to conventional methods ofdrug production.

The tablet, capsule, granule and pill for oral administration can beprepared using excipienl (e.g., sucrose, lactose, glucose, starch,mannitol and the like), binder (e.g., syrup, acacia, gelatin, sorbitol,tragacanth, methylcellulose, polyvinylpyrrolidone and the like),disintegrant (e.g., starch, carboxymethylcellulose or calcium saltthereof, microcrystalline cellulose, polyethylene glycol and the like),lubricant (e.g., talc, magnesium stearate, calcium stearate, silica andthe like), glidant (e.g., sodium lauryl sulfate, glycerol and the like),and the like.

The injection, aerosol agent, syrup, liquid, emulsion and suspension canbe prepared using a solvent for the active ingredient (e.g., water,ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol,polyethylene glycol and the like), a surfactant (e.g., sorbitan fattyacid ester, polyoxyethylenesorbitan fatty acid ester, polyoxyethylenefatty acid ester, polyoxyethylene ether of hydrogenated caster oil,lecithin and the like), a suspending agent (e.g., cellulose derivativessuch as carboxymethylcellulose sodium salt, methylcellulose and thelike, natural gums such as tragacanth, acacia and the like), apreservative (e.g., p-hydroxybenzoate, benzalkonium chloride, sorbateand the like), and the like. A suppository can be prepared using, forexample, polyethylene glycol, lanolin, coconut oil and the like.

The dose of the pyridazinone compound (I) and a salt thereof can bedetermined as appropriate according to the age, body weight, diseasestate and the like of the patient. It is generally 0.001 mg-5 g/day,preferably 0.005-1000 mg/day, for an adult (human), which isadministered in one to several doses a day.

When the pyridazinone compound (I) or a pharmacologically acceptablesalt thereof is used as a potentiator of the angiogenic effect of a drughaving such effect, the pyridazinone compound in the present inventionand the drug having an angiogenic effect are administered in such amanner that they are both present in the body during the same period oftime. The use and dose of the drug having an angiogenic effect are freeof limitation as long as they fall within the known ranges. They may beprepared into a single pharmaceutical preparation or separately intoindividual preparations. When they are separate preparations, theadministration route and dose may be the same or different.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph showing the neovascularized blood vessel at day 7of the test in a rat sponge model group administered with a vehicle.

FIG. 2 is a photograph showing the neovascularized blood vessels at day7 of the test in a rat sponge model group administered with compound A.

FIG. 3 shows the amount of hemoglobin in sponge in a rat sponge model,indicating the angiogenesis-promoting effect of compound A.

FIG. 4 is a photograph showing the neovascularized blood vessels at day4 of the test in a rat sponge model group 1 administered with aBSA-physiological saline solution.

FIG. 5 is a photograph showing the neovascularized blood vessels at day4 of the test in a rat sponge model group 2 administered solely with abasic fibroblast growth factor (b-FGF).

FIG. 6 is a photograph showing the neovascularized blood vessels at day4 of the test in a rat sponge model group 3 co-administered with b-FGFand compound A.

FIG. 7 shows the amount of hemoglobin in sponge in a rat sponge model,indicating angiogenic potency of b-FGF by compound A.

FIG. 8 shows the relationship between the dose and angiogenic efficacyby compound A in a rat sponge model.

EXAMPLES

The present invention is explained in detail in the following Examplesand Experimental Examples. The invention is not limited by theseExamples in any way.

Experimental Example 1

Promotion of Angiogenesis by Compound A

Method:

Rats were anesthetized by intraperitoneal administration of sodiumpentobarbital (50 mg/kg), and the dorsal median line was incised forabout 1 cm and an air pocket was made subcutaneously at about 2.5 cmtoward the tail side with a Kocher clamp. A hemostatic gelatin sponge(Spongel®, 10 mm×10 mm×7 mm; manufactured by Yamanouchi PharmaceuticalCo., Ltd.) impregnated with physiological saline was embedded therein.The opening was sutured and antisepticized to give a test animal model.

As a reagent, compound A(4-bromo-6-[3-(4-chlorophenyl)-propoxy]-5-(3-pyridylmethylamino)-3-(2H)-pyridazinonehydrochloride, 100 mg) produced by a conventional method was suspendedin 0.5% methylcellulose solution (100 ml) in a mortar and used.

As a control, a vehicle (0.5% methylcellulose solution) was used. Thevehicle was obtained by dissolving methylcellulose (5 g, manufactured byKishida Chemical Industries, Ltd.) in distilled water (1000 ml).

The reagent (compound A) and the vehicle were orally administeredrepeatedly from the day of sponge embedding at a dose of 10 ml/kg once aday for 4 days or 7 days. The administration was performed 30 minutesbefore anesthetizing the animal on the very day of embedding, and thesponge was removed on the next day of the final administration.

After 4 days or 7 days from the embedding, an excess amount ofpentobarbitalwas intravenously injected to the animals for euthanasia.The back was opened, and the tissue surrounding the embedded sponge wasremoved and the surface of the sponge was photographed. The sponge wastaken out and placed in a 0.1M aqueous ammonia (2 ml), which was stoodfor 4 hr to extract hemoglobin in the sponge. The extract (100 μl) wastaken, and hemoglobin was quantitated using an assay kit (hemoglobinB-TESTWAKO; manufactured by Wako Pure Chemical Industries, Ltd.) andused as the index of angiogenesis. The amount of hemoglobin in thesponge was calculated by the following formula.

Amount of hemoglobin in sponge (mg/sponge)=hemoglobin (mg) in extract(100 μl)×20 (total extract 2 ml)

The obtained data were expressed in mean±standard error. For theevaluation of the angiogenic effect, an unpaired t-test was performedusing the animals administered with the drug for 4 days or 7 days andrespective vehicle groups as control to examine significant difference.The significance was ascribed at less than 5% risk rate.

Results:

1. Observation of Photograph

Both the reagent (compound A) administration group and vehicleadministration group showed an increase of neovascularized blood vesselson the sponge surface at day 4 and day 7 of the test in proportion tothe number of days lapsed from the initiation of the test. At day 7 ofthe test, the reagent (compound A) administration group (FIG. 2) showedmore neovascularized blood vessels than in the vehicle administrationgroup (FIG. 1).

2. Amount of Hemoglobin in Sponge

The results are shown in Table 1 and FIG. 3. Both the reagent (compoundA) administration group and vehicle administration group showed anincrease in the amount of hemoglobin in sponge at day 4 and day 7 of thetest, in proportion to the number of days lapsed from the initiation ofthe test. At day 7 of the test, the reagent (compound A) administrationgroup showed a significant increase as compared to the vehicleadministration group.

TABLE 1 Hemoglobin in sponge (mg/sponge) 4 days 7 days Drug afterembedding after embedding Vehicle 6.216 ± 0.903 (9)  9.585 ± 0.774 (10)Reagent (compound A) 6.255 ± 0.807 (10) 16.351 ± 1.836 ** (9) ( ):number of animals **:p < 0.01 relative to vehicle administration group,unpaired t-test

Experimental Example 2

Potentiation of Angiogenic Effect of b-FGF by Compound A

Method:

The test animal models were prepared in the same manner as inExperimental Example 1.

As a reagent, compound A(4-bromo-6-[3-(4-chlorophenyl)-propoxy]-5-(3-pyridylmethylamino)-3-(2H)-pyridazinonehydrochloride, 50 mg) produced by a conventional method was suspended in0.5% methylcellulose solution (100 ml) in a mortar and used.

The vehicle (0.5% methylcellulose solution) was obtained by dissolvingmethylcellulose (5 g, manufactured by Kishida Chemical Industries, Ltd.)in distilled water (1000 ml).

A 0.1% bovine serum albumin (BSA)-physiological saline solution wasprepared by dissolving BSA (0.1 g, Sigma) in physiological saline (100Ml).

A b-FGF solution was prepared by dissolving recombinant b-FGF (20 μg,manufactured by BTI) in 0.1% BSA-physiological saline solution (2 ml).

A hemostatic gelatin sponge was the same as that used in ExperimentalExample 1.

The test group was divided into 3 groups. A sponge wetted with 100 μl of0.1% BSA-physiological saline solution was embedded in group 1. A sponge(1 μg b-FGF/sponge) wetted with b-FGF solution (100 μl) was embedded ingroup 2 and group 3.

The vehicle was orally administered to group 1 and group 2, and thereagent (compound A) was orally administered to group 3 repeatedly fromthe day of sponge embedding at the dose of 10 ml/kg twice a day for 4days.

In every test group, the administration began from the evening (singleadministration) of the very day of embedding. The time of administrationof the drug was around 9 a.m. for the first administration and around 7p.m. for the second administration. In consideration of the effect ofthe drug, the drug was not administered on the very day of spongeremoval (7 times of administration in total).

After 4 days from the embedding, an excess amount of pentobarbital wasintravenously injected to the animals for euthanasia. The back wasopened, and the tissue surrounding the embedded sponge was removed andthe surface of the sponge was photographed. The sponge was taken out andhemoglobin in the sponge was calculated in the same manner as inExperimental Example 1.

The obtained data were expressed in mean±standard error. For theevaluation of the angiogenic effect, a multiple comparison test by Tukeymethod was performed to examine significant difference. The significancewas ascribed at less than 5% risk rate.

Results:

1. Observation of Photograph

The results are shown in FIG. 4, FIG. 5 and FIG. 6. At day 4 of thetest, group 2 (b-FGF single administration group) visually showed moreneovascularized blood vessels than in group 1 (0.1% BSA-physiologicalsaline solution group), and group 3 (b-FGF and reagent (compound A, 5mg/kg) co-administration group) showed still more neovascularized bloodvessels than in group 2.

2. Amount of Hemoglobin in Sponge

The results are shown in Table 2 and FIG. 7. The group 3 (b-FGF andreagent (compound A, 5 mg/kg) co-administration group) showed asignificant increase in hemoglobin content as compared to group 1 (0.1%BSA-physiological saline solution group) and group 2 (b-FGF singleadministration group).

TABLE 2 Hemoglobin in sponge (mg/sponge) Drug at 4 Test In-sponge daysafter group Oral administration administration embedding Group 1 VehicleBSA-physiological  5.503 ± saline 0.562 (10) Group 2 Vehicle b-FGF 7.285 ± 0.715 (10) Group 3 Reagent (compound A) b-FGF 14.995 ± 2.307++,** (10) ( ): number of animals, ++:p < 0.01 relative to group 1, **:p< 0.01 relative to group 2 (Tukey method)

Experimental Example 3

Relationship Between Dose and Angiogenesis Promotion by Compound A

Method:

The test animal models were prepared in the same manner as inExperimental Example 1.

As a reagent, compound A(4-bromo-6-[3-(4-chlorophenyl)-propoxy]-5-(3-pyridylmethylamino)-3-(2H)-pyridazinonehydrochloride, 35 mg) produced by a conventional method was suspended in0.5% methylcellulose solution (70 ml) in a mortar and used as a 5 mg/kgadministration reagent.

This suspension was diluted two-fold and 5-fold with a vehicle (0.5%methylcellulose solution) to give 2.5 mg/kg administration reagent and 1mg/kg administration reagent (respective dose 10 ml/kg). The vehicle(0.5% methylcellulose solution) was used as a control. The vehicle wasobtained by dissolving methylcellulose (5 g, manufactured by KishidaChemical Industries, Ltd.) in distilled water (1000 ml).

Each reagent (compound A) and the vehicle were orally administeredrepeatedly (7 times in total) from the day of sponge embedding at a doseof 10 ml/kg twice a day for 4 days. The sponge was removed on the nextday of the final administration, and hemoglobin in the sponge wascalculated in the same manner as Experimental in Example 1.

Each group contained 814 9 animals and the obtained data were expressedin mean±standard error. For the evaluation of the angiogenic effect, aDunnett test was performed using the vehicle administration group as acontrol to examine significant difference. The significance was ascribedat less than 5% risk rate.

Results:

The results are shown in FIG. 8. As compared to the vehicleadministration group, 2.5 mg/kg administration group and 5 mg/kgadministration group showed a significant increase in hemoglobin amount.

In the 5 mg/kg administration group, the effect tended to weakensomewhat, though a significant difference was found. This is postulatedto be attributable to a decrease in blood flow due to hypotensiveaction, since the dose (5 mg/kg) of compound A causes hypotensive actionin rat, based on vasodilating action.

This has clarified that compound A shows superior angiogenesis promotioneffect at a dose substantially free from hypotensive action.

Experimental Example 4

Toxicity

The acute toxicity (LD₅₀) of compound A was not less than 2 g/kg by theoral administration to rat and dog, and the compound was found to beextremely low toxic.

From the above test results, it is evident that the pyridazinonecompound (I) and a salt thereof show superior angiogenesis-promotingeffect and potentiation of the angiogenic effect of a drug having sucheffect, and are low toxic.

Example 1 (tablet)

The following ingredients were mixed by a conventional method andprepared into sugar-coated tablets containing 50 mg of the activeingredient per tablet.

Compound A 10 g lactose 20 g starch 5 g magnesium stearate 0.1 g calciumcarboxymethylcellulose 7 g total 42.1 g

Example 2 (capsule)

The following ingredients were mixed by a conventional method and filledin gelatin capsules to give capsules containing 50 mg of the activeingredient per capsule.

Compound A 10 g lactose 20 g microcrystalline cellulose 10 g magnesiumstearate  1 g total 41 g

Example 3 (ointment)

The following ingredients were mixed by a conventional method to give a1 wt% ointment.

Compound A 1 g olive oil 20 g white petrolatum 79 g total 100 g

Example 4 (aerosol suspension)

The following ingredients (A) were mixed and the obtained mixed solutionwas charged in a container equipped with a valve. A propellant (B) waspressed therein from a valve nozzle at 20° C. to about 2.46-2.81 mg/cm²gauge pressure to give an aerosol suspension.

(A)Compound A  0.25 wt % isopropyl myristate  0.10 wt % ethanol 26.40 wt% (B)1,2-dichlorotetrafluoroethane and 73.25 wt %1-chloropentafluoroethane (60-40 wt %)

Industrial Applicability

The pyridazinone compound (I) and pharmacologically acceptable saltthereof in the present invention promote angiogenesis and potentiate theangiogenic effect of a drug having such effect, and are useful as anangiogenesis promoter and potentiator. Therefore, they are effective forthe promotion of healing of various diseases wherein angiogenesis playsan important role, such as promotion of wound healing, promotion ofadhesion after skin implantation, promotion of healing after re-sutureon quadruple amputation, trichogenous promotion and the like.

This application is based on a patent application No. 232644/1997 filedin Japan, the contents of which are hereby incorporated by reference.

What is claimed is:
 1. A method of promoting angiogenesis, whichcomprises administering a pyridazinone compound of the formula (I)

wherein R¹, R² and R³ are each independently a hydrogen atom or a loweralkyl, X is a halogen atom, cyano or a hydrogen atom, Y is a halogenatom, trifluoromethyl or a hydrogen atom, and A is C₁-C₈ alkyleneoptionally substituted by hydroxyl group, or a pharmacologicallyacceptable salt thereof.
 2. The method of claim 1, wherein thepyridazinone compound is a compound of the formula (I) wherein R¹ and R²are each a hydrogen atom, R³ is a hydrogen atom or alkyl having 1 to 4carbon atoms, X is a halogen atom, Y is a halogen atom or a hydrogenatom, and A is C₁-C₅ alkylene optionally substituted by hydroxyl group.3. The method of claim 1, wherein the pyridazinone compound of theformula (I) is4-bromo-6-[3-(4-chlorophenyl)-propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone.4. A method of potentiating an angiogenic effect of a drug having sucheffect, which comprises administering a pyridazinone compound of theformula (I)

wherein R¹, R² and R³ are each independently a hydrogen atom or a loweralkyl, X is a halogen atom, cyano or a hydrogen atom, Y is a halogenatom, trifluoromethyl or a hydrogen atom, and A is C₁-C₈ alkyleneoptionally substituted by hydroxyl group, or a pharmacologicallyacceptable salt thereof.
 5. The method of claim 4, wherein thepyridazinone compound is a compound of the formula (I) wherein R¹ and R²are each a hydrogen atom, R³ is a hydrogen atom or alkyl having 1 to 4carbon atoms, X is a halogen atom, Y is a halogen atom or a hydrogenatom, and A is C₁-C₅ alkylene optionally substituted by hydroxyl group.6. The method of claim 4, wherein the pyridazinone compound of theformula (I) is4-bromo-6-[3-(4-chlorophenyl)-propoxy]-5-(3-pyridylmethylainino)-3(2H)-pyridazinone.7. The method of claim 4, wherein the drug having the angiogenic effectis a growth factor.
 8. The method of claim 7, wherein the growth factoris a basic fibroblast growth factor.